The present invention relates to a process for preparing 3-halogenated methylcephem compound of high reactivity which can be used in place of 7-aminocephalosporanic acid (7-ACA) generally used as a conventional starting material. The invention also relates to a process for preparing 3-thiomethylcephem compound which is an important intermediate of various antibiotic substances.
3-Thiomethylcephem compounds prepared in the present invention are useful intermediates of antibiotic substances represented by cefazolin and ceftriaxone. These antibiotic substances are excellent antibacterial agents having a wide range antibacterial spectrum as disclosed in, for example, Handbook of Latest Antibiotics, 9th ed., Katsuji Sakai, P. 59 and P. 73. 
As a process for preparing 3-halogenated methylcephem compounds, there has been usually employed a process in which, by utilizing 7-aminocephalosporanic acid (7-ACA) generally used in preparing cephalosporanic antibiotic substances, amino group and carboxylic acid are protected with silyl group, and the acetoxy group is halogenated, followed by deprotection of the silyl protecting groups at the 7-position and 4-position. In this process, however, an expensive silyl reagent of not less than 2 equivalents is required, and a very expensive reagent such as trimethylsilyl iodide is needed in the conversion of acetoxy group into halogen atom. Since these reagents are highly sensitive to water, it is necessary to maintain the reaction system free from water. This process is therefore unsuitable industrially.
As a process for preparing 3-thiomethylcephem compounds, there has been usually employed a process in which 7-aminocephalosporanic acid (7-ACA) is directly reacted with thiol or its salt. This process, however, constrains the reaction at high temperatures, because the reactivity of acetoxy group is low. In this event, not only a decrease in reaction yield and an increase in by-product are unavoidable, but also isolation and purification operation is complicated. That is, this process is not always advantageous industrially. Accordingly, there has been a desire for a process for preparing 3-halogenomethylcephem compounds or 3-thiomethylcephem compounds, which is industrially feasible with ease, and is highly practical.
An object of the present invention is to establish an industrially feasible process for preparing 3-halogenomethylcephem compounds, and provide a process for preparing 3-thiomethylcephem compounds by using 3-halogenomethylcephem compound as a starting material.
The present invention provides a process for preparing 3-halogenomethylcephem compound of the formula (2) or its salt, comprising a carboxylic acid protecting group at the 4-position of 7-amino-3-halogenomethylcephem compound of the formula (1) or its salt is deprotected with phenol derivative 
wherein X1 is halogen atom; and R1 is benzyl group which has on a phenyl ring an electron-donating group as a substituent, or diphenylmethyl group which may have an electron-donating group on a phenyl ring 
wherein X1 is halogen atom.
The present invention also provides a process for preparing 3-thiomethylcephem compound of the formula (4) or its salt, comprising 3-halogenomethylcephem compound of the formula (2) or its salt is reacted with thiol compound or its salt of the formula (3) 
wherein X1 is halogen atom
R2Sxe2x80x94Mxe2x80x83xe2x80x83(3)
wherein R2 is nitrogen-containing aromatic heterocyclic group which may have a substituent; and M is hydrogen atom, alkali metal or alkaline earth metal 
The present invention further provides a process for preparing 3-thiomethylcephem compound or its salt, comprising a carboxylic acid protecting group at the 4-position of 7-amino-3-halogenomethylcephem compound of the formula (1) is deprotected with phenol derivative and, without isolation, reacted with thiol compound or its salt of the formula (3), thereby obtaining 3-thiomethylcephem compound of the formula (4) or its salt.
The conventional process for preparing 3-thiomethylcephem compounds by employing 7-ACA as a starting material, suffers from the drawbacks of the low reaction yield and the formation of by-product, resulting in an unsatisfactory process. To establish an industrially feasible process, the inventors regarded that these drawbacks were due to the low reactivity of the acetoxy group at the C-3xe2x80x2 position, and employed 3-halogenomethylcephem compounds which have at the C-3xe2x80x2 position a halogen atom having a higher reactivity, as a starting material. However, any practical process for preparing these compounds were not known. Therefore, by utilizing a deprotection reaction in which phenol derivative is used for the carboxyl group at the 4-position of 7-amino-3-halogenomethylcephem compound, the inventors established an industrially feasible process for preparing 3-halogenomethylcephem compounds, as well as a process with which 3-thiomethylcephem compound is prepared from 7-amino-3-halogenomethylcephem compound at high purity and high yield.
The process of the invention enables to smoothly proceed the reaction at environmental temperature, minimize by-product, and facilitate the isolation and purification of a desired product. That is, this process has a higher industrial practicality than the conventional reaction using the 7-ACA as a starting material.
Also, the process of the invention enables to prepare 3-halogenomethylcephem compounds and 3-thiomethylcephem compounds at high purity and high yield, in such a manner as to be industrially feasible with ease.
Examples of the groups mentioned in the specification are as follows. Exemplary of the halogen atom are fluorine atom, chlorine atom, bromine atom and iodine atom. Examples of lower alkyl group are straight-chain or branched-chain C1-C4 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Exemplary of aryl group are phenyl and naphthyl.
Examples of electron-donating group substituted on the phenyl ring of benzyl group or diphenylmethyl group represented by R1 are hydroxy; methyl, ethyl, tert-butyl and like lower alkyl groups; and methoxy, ethoxy and like lower alkoxy groups. The diphenylmethyl group includes a type of the group which is a substituted or unsubstituted phenyl group bonded in the molecule via methylene chain or hetero-atom. There are, for example, p-methoxybenzyl, diphenylmethyl, 3,4,5-trimethoxybenzyl, 3,5-dimethoxy-4-hydroxybenzyl, 2,4,6-trimethylbenzyl and ditolylmethyl.
Examples of nitrogen-containing aromatic heterocyclic group which may have a substituent represented by R2 are triazolyl, triazinyl, thiadiazolyl, tetrazolyl and benzothiazolyl. Examples of substituent which can substitute for the heterocyclic group are lower alkyl group, sulfo lower alkyl group, carboxy lower alkyl group, amino lower alkyl group, lower alkyl substituted amino lower alkyl group and hydroxy lower alkyl group.
Examples of thio group represented by R2Sxe2x80x94 are thio substituents among the known substituents at the 3-position of cephalosporin as described in USAN and the USP dictionary of drugs names. There are, for example, 1,2,3-triazol-4-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, 1-methyltetrazol-5-ylthio, 1-sulfomethyltetrazol-5-ylthio, 1-carboxymethyltetrazol-5-ylthio, 1-(2-dimethylaminoethyl)tetrazol-5-ylthio, 1,3,4-thiadiazol-5-ylthio, 1-(2-hydroxyethyl)tetrazol-5-ylthio, 3-methyl-1,3,4-triazine-5,6-dione-2-thio, and benzothiazol-2-thio.
Examples of alkali metal or alkaline earth metal represented by M are lithium, sodium, potassium, calcium and magnesium.
The 3-halogenomethylcephem compounds (1) used as a starting material in the invention can be easily prepared in the following manner that 7-phenylacetamide-3-chloromethylcephem-4-carboxylate prepared by a process as described in the literature of Torii et al., Tetrahedron Lett., 23, 2187 (1982), is subjected to deprotection of the 7-position amide side chain, by a process as described in RECENT ADVANCES IN THE CHEMISTRY OF xcex2-Lactam Antiobiotics pp. 109-124, 1980 edited by G. I. Gregory.
In the present invention, the compounds (1) include the salt of the 7-position amino group. Examples of the salt are hydrohalogenic acid salt such as hydrochloride, hydrobromide and hydroiodide; sulfate; hydroperhalogenic acid salt such as perchlorate and periodate; and sulfonates such as p-toluenesulfonate.
Examples of the phenol derivative used in the present invention are phenol, m-cresol, o-cresol and p-cresol. Any other compound which has a phenolic hydroxyl group can be used. The amount of a phenol derivative used in the reaction as described is 1 to 1000 equivalents, preferably 5 to 100 equivalents, to the compound (1). In order to facilitate the reaction, acid can be used as required. Examples of the acid are mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid and trifluoroacetic acid. Any other one which is an acid substance can be used. The reaction temperature depends on the kind of the compound (1) and the kind of the phenol derivative, but it is usually 5 to 80xc2x0 C., preferably 15 to 50xc2x0 C. The reaction time depends on the kind of the compound (1), the kind of the phenol derivative and the reaction temperature, but it is usually terminated in 1 to 5 hours. If some material remains, the reaction time may be extended, which causes no problems.
In the present invention, 3-thiomethylcephem compound of the formula (4) or its salt is prepared by reacting 3-halogenomethylcephem compound of the formula (2) or its salt with thiol compound or its salt of the formula (3).
As exemplary of the salt of the compound (2), there are the salt of the 7-position amino group, and the salt of the 4-position carboxylic acid. Examples of the salt of the 7-position amino group are hydrohalogenic acid salt such as hydrochloride, hydrobromide and hydroiodide; sulfate; hydroperhalogenic acid salt such as perchlorate and periodate; and sulfonates such as p-toluenesulfonate. Examples of the salt of the 4-position carboxylic acid are alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium; and aluminum salt. Also, salt can be formed from ion-exchange resin, together with the 7-position amino group or the 4-position carboxylic acid.
As thiol compound of the formula (3), an alkali metal salt or alkaline earth metal salt can be used, and thiol compound (when M is H) can also be used. In this case, the reaction may be conducted by the conjoint use of a variety of bases, depending on the reaction conditions.
Examples of bases used herein are basic ion-exchange resin; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; ammonia; tertiary amines substituted by a lower alkyl group such as methyl, ethyl, propyl, isopropyl or t-butyl, and quaternary ammonium salt thereof. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 30 equivalents, to the compound (2). The above-mentioned bases may be mixed together as required.
Examples of solvents are water, ketones such as acetone; ethers such as THF and dioxane; hydrocarbon halides such as methylene chloride and chloroform; nitrites such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile and valeronitrile; and dimethyl sulfoxide. These can be used singly or in a mixture of at least two of them. Alternatively, it is possible to use a mixed solvent in which the above solvent is used mainly and other usual solvents are added thereto. As the usual solvents, there are, for example, lower alkyl esters of lower carboxylic acids such as methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate and ethyl propionate; ethers such as diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methylcellosolve and dimethoxyethane; cyclic ethers such as tetrahydrofuran and dioxane; substituted or unsubstituted aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and anisole; hydrocarbons such as pentane, hexane, heptane and octane; cycloalkanes such as cyclopentane, cyclohexane, cycloheptane and cyclooctane; and halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride and carbon tetrachloride. Particularly preferred solvent are mixed solvents of which main solvent is water, dimethylformamide, 1-methyl-2-pyrrolidinone or dimethyl sulfoxide.
These solvents are used in an amount of about 0.5 to 200 liter, preferably about 1 to 50 liter, per 1 kg of the compound (2). The reaction is conducted in the range of xe2x88x9210 to 80xc2x0 C., preferably 0 to 50xc2x0 C.
In the present invention, 3-thiomethylcephem compound of the formula (4) or its salt can be obtained in the following manner that a carboxylic acid protecting group at the 4-position of 7-amino-3-halogenomethylcephem compound of the formula (1) is deprotected with phenol derivative and, without isolation, reacted with thiol compound or its salt of the formula (3). The deprotection and the reaction with a thiol compound or its salt, can be conducted in the same manner as described above.
The compound of the formula (4) can be obtained as an approximately pure product, by performing, after the reaction is terminated, the usual extraction or crystallization. It is, of course, possible to purify by any other method.
The present invention will be described in further detail by the following examples, a comparative example and a reference example.
Preparation of 3-halogenomethylcephem compounds